Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study

Our plain-English summary of Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study, by P. Schwarzenberger, P. Byrne, R. Gaumer, et al (Cancer Gene Therapy, 2011).

The study

• Authors: P. Schwarzenberger, P. Byrne, R. Gaumer, J. Norton, L. Harrison, A. Marrogi, J.K. Kolls
• Journal: Cancer Gene Therapy
• Published: 2011;18(12):906-12
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is an incurable cancer of the pleura with a life expectancy of less than 1 year. On the basis of in vivo efficacy seen with the herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene-modified PA1STK cell line and ganciclovir (GCV) in a murine model of mesothelioma, a first in humans, clinical trial was designed for this therapeutic concept. The study was a phase I clinical trial using direct infusion of escalating doses of HSVtk suicide gene-modified PA1STK cells directly into tumor-associated pleural effusions followed by 7 days of intravenous GCV infusion. Therapeutic levels of GCV in both serum and pleura were achieved within 1 h, and GCV trough levels remained above the therapeutic threshold for the duration of GCV treatment. The treatment was well tolerated without any Grade 3 or 4 toxicity observed. Significant inductions of both Th1 and Th2 cytokines up to 20-fold over baseline were observed. No significant differences were seen between serum and pleura cytokine profiles, with the exception of interleukin-10, which was consistently elevated in the pleura specimens. No objective radiographic responses were observed. The data indicate significant immunological responses and validate the principal anti-tumor mechanisms observed in preclinical models of mesothelioma in a human clinical trial.

In plain English

This first-in-humans phase I trial tested a gene therapy in 15 untreated patients with malignant mesothelioma of the pleura, recruited 1997 to 1999. Irradiated PA1STK cells, a human ovarian cancer line carrying a herpes virus 'suicide gene', were infused by catheter into the fluid around the lung. The first six patients had one infusion, with doses rising between groups; the other nine had three rising doses. Each infusion was followed by a week of intravenous ganciclovir, which the gene makes toxic. No Grade 3 or 4 side effects were recorded; Grade 1 or 2 fever, fast heartbeat, malaise and breathlessness occurred. Within 1 hour, chest-fluid ganciclovir was comparable to blood levels and stayed at or above target. Immune signalling proteins rose up to 20-fold over baseline. No objective tumor responses were seen on scans. Disease was stable in 9 patients at 3 months and in 3 at 6 months. Median survival from treatment start was 7.7 months, which the authors called within the expected range. The authors called the approach feasible but noted the small trial had no comparison group. The patients' own asbestos exposure histories were not reported.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I dose-escalation clinical trial, with no control group
• Who was studied: 15 previously untreated patients with malignant mesothelioma of the pleura and an accessible pleural effusion, recruited 1997 to 1999 under approval of the LSU Institutional Review Board. There were 14 men and 1 woman; 8 were stage III and 7 stage IV. Histology was epithelial in 11, sarcomatoid in 3 and biphasic in 1. Median age was 63.6 years (range 39 to 82).
• Exposure: Not an asbestos exposure study. The article notes in its introduction that mesothelioma is related to previous asbestos exposure, but it does not report the participants' exposure histories. The intervention was irradiated PA1STK cells (a human ovarian carcinoma cell line carrying the herpes simplex virus thymidine kinase gene) infused into the pleural cavity. Doses ranged from 3 x 10^7 to 1 x 10^10 cells: patients 1 to 6 received one infusion and patients 7 to 15 received three. Each infusion was followed by intravenous ganciclovir 5 mg/kg every 12 hours for 14 doses.
• Main results:
  • No Grade 3 or 4 toxicity was recorded in the 15 patients. Recorded events were fever (Grade I in 6, Grade II in 3), tachycardia (Grade I in 4), malaise (Grade I in 7) and dyspnea (Grade I in 4, Grade II in 2).
  • No objective tumor responses were seen on imaging. Disease was stable in 9 patients at 3 months and in 3 patients at 6 months.
  • Median overall survival from the start of treatment was 7.7 months (range 3 to 14 months). Median time to disease progression was 5.1 months (range 3 to 12 months).
  • Within 1 hour, ganciclovir in the pleural cavity reached levels comparable to serum. Levels stayed at or above the 2.0 micromolar therapeutic threshold during treatment.
  • Th1 cytokines rose up to 20-fold over baseline after infusion, in both blood and pleural fluid.
  • Pleural IL-10 increased by up to sevenfold and was significantly higher than serum IL-10, which increased at most threefold.
  • The dose of infused cells did not significantly influence pleural ganciclovir concentration.
• The authors' conclusion: The authors concluded that gene-modified cell-based therapy given into the chest cavity is feasible and that ganciclovir reaches therapeutic levels in the target tissues. They also noted that median survival was within the range expected for the disease.
• Limitations the authors state:
  • As a phase I study, it had few patients and no control arm, so the information gained is limited.
  • Efficacy could not be accurately determined because of the small number of patients.
  • Response assessment in mesothelioma is difficult and often unreliable.
  • The cytokine response might have been caused simply by infusing donor cells, although the authors believe the gene-drug effect is required.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleura, Life Expectancy, Clinical Trial, Pleural Effusion, Cytokine.

Related studies

• Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model — E.S. Lambright, S.D. Force, et al. (2000)
• Gene-modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma — L.H. Harrison, P.O. Schwarzenberger, et al. (2000)
• Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer — H.C. Hwang, W.R. Smythe, et al. (1995)
• Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and — R. Hustinx, C.Y. Shiue, et al. (2001)
• Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy — W.R. Smythe, H.C. Hwang, et al. (1995)
• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)

Browse more research in Cancer Gene Therapy, or return to medical research.